Catalyst complex with carbene ligand

ABSTRACT

Catalytic complexes including a metal atom having anionic ligands, at least one nucleophilic carbene ligand, and an alkylidene, vinylidene, or allenylidene ligand. The complexes are highly stable to air, moisture and thermal degradation. The complexes are designed to efficiently carry out a variety of olefin metathesis reactions.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/481,401, filed on Sep. 9, 2014, now pending, which is a continuationof U.S. patent application Ser. No. 13/750,265, filed Jan. 25, 2013, nowU.S. Pat. No. 8,859,779, which is a continuation of U.S. patentapplication Ser. No. 13/041,573, filed Mar. 7, 2011, now abandoned,which is a continuation of U.S. patent application Ser. No. 12/622,225,filed Nov. 19, 2009, now U.S. Pat. No. 7,902,389, which is acontinuation of U.S. patent application Ser. No. 09/392,869, filed Sep.9, 1999, now U.S. Pat. No. 7,622,590, which claims priority from U.S.Provisional Application Ser. No. 60/115,358, filed Jan. 8, 1999 and U.S.Provisional Application Ser. No. 60/099,722, filed Sep. 10, 1998. Thedisclosures of these applications are incorporated by reference in theirentirety.

STATEMENT AS TO FEDERALLY SPONSORED RESEARCH

This invention was made with Government support under Grant No.CHE-963611 awarded by the National Science Foundation. The Governmenthas certain rights in this invention.

BACKGROUND OF THE INVENTION

The invention relates to metal carbene complexes. More particularly, itrelates to catalyst systems comprising metal carbene complexes.

Catalysts previously known in the art are described in, for example,U.S. Pat. No. 5,312,940 to Grubbs et al. These catalysts includebis(phosphine) complexes which involve the use of costly phosphine (PR₃)ligands. The stabilities of such systems, as determined by, for example,P—C bond degradation at elevated temperature, are limited. Also, therates at which bis(phosphine) catalysts carry out particular reactionsare limited. Thus, industrial applications involving large-scalesyntheses are not as efficient as they could be.

Previously available catalytic systems are also limited in their abilityto make highly substituted ring-closing metathesis (RCM) products. Thus,bis(phosphine) catalysts cannot reliably close dienes to maketri-substituted cyclic alkenes, and they fail to make tetra-substitutedcyclic alkenes in all but a few cases. Although Schrock catalysts areavailable to carry out this type of reaction, such systems are quitesensitive.

Thus there exists in the art a need for a generally air- andmoisture-sensitive catalyst system able to carry out RCM reactionsefficiently and reliably, and also without excessive thermalsensitivity.

SUMMARY OF THE INVENTION

The invention provides catalysts including metal carbene complexes whichare useful for synthetic chemical reactions. The catalysts include atleast one bulky nucleophilic carbene ligated to the metal center.Methods of making such catalysts, and ligands useful for such catalystsare also provided in the present invention.

The inventive catalytic complexes are thermally stable, have highreaction rates, and are air- and moisture-stable. The catalysts of theinvention are easy to synthesize, have high catalytic activity, and arerelatively inexpensive, due to the availability of the nucleophiliccarbene ligand. The catalysts are useful in the facilitation of chemicalreactions, including applications in the pharmaceutical industry, finechemical synthesis, and the synthesis of polymers.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the present invention, suitable methods andmaterials are described below. In case of conflict, the presentspecification, including definitions, will control. In addition, thematerials, methods, and examples are illustrative only and not intendedto be limiting.

Other features and advantages of the invention will be apparent from thefollowing detailed description, and from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a general structure of a first particular embodiment of acatalytic complex, having a first ligation pattern.

FIG. 1B is a general structure of a first particular embodiment of acatalytic complex, having a second ligation pattern.

FIG. 1C is a general structure of a first particular embodiment of acatalytic complex, having a third ligation pattern.

FIG. 2A is an example of a nucleophilic carbene ligand which can beutilized in certain embodiments of the present invention.

FIG. 2B is a particular nucleophilic carbene which can be utilized incertain embodiments of the invention.

FIG. 2C is a particular nucleophilic carbene which can be utilized incertain embodiments of the invention.

FIG. 3A is a general structure of a second particular embodiment of acatalytic complex, having a first ligation pattern.

FIG. 3B is a general structure of a second particular embodiment of acatalytic complex, having a second ligation pattern.

FIG. 3C is a general structure of a second particular embodiment of acatalytic complex, having a third ligation pattern.

FIG. 4 is an ORTEP diagram of the crystal structure of Cp*Ru(IMes)Cl.

FIG. 5 is an ORTEP diagram of the crystal structure of Cp*Ru(PCy₃)Cl.

FIG. 6 is an ORTEP diagram of the crystal structure of Cl₂Ru(PCy₃)(IMes)(═CHPh).

DETAILED DESCRIPTION

The invention includes a catalytic complex for the carrying out ofchemical reactions. The complex includes a metal atom and variousligands. A particular embodiment of the catalytic complex is depicted inFIGS. 1A, 1B and 1C.

Making reference to FIG. 1A, metal atom M can be a transition metalgenerally having an electron count of from 14 to 18. Particular metalsof this description which have been found useful in the presentinvention include ruthenium and osmium.

Ligated to metal atom M are a number of ligands. At least one of theseligands is a carbene ligand, which is functionally an olefin metathesisactive fragment, having a carbon atom C¹ which can be further bonded upto two other groups. The bond from metal atom M to carbon atom C¹ can beformulated as the double bonded M=C¹, although other canonical forms areevidently involved, as detailed in Cotton and Wilkinson's AdvancedInorganic Chemistry, 5th Edition, John Wiley & Sons, New York (1980),pp. 1139-1140.

As noted, carbon atom C¹ can further bonded to up to two other groups, Rand R¹, and in this case the olefin metathesis active fragment isreferred to as an alkylidene. These R and R¹ groups are independentlyselected from a large number of atoms and substituents. These includehydrogen, alkyl groups having from 1 to 20 carbon atoms (such as methyl,ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and thelike). Also possible as either R or R¹ are alkenyl or alkynylsubstituents having from 2 to 20 carbon atoms. The groups R and R¹ canalso include alkoxycarbonyl substituents having from 2 to 20 carbonsatoms, aryl groups, carboxylate substituents having from 1 to 20 carbonatoms, alkoxy substituents having from 1 to 20 carbon atoms, alkenyloxyor alkynyloxy substituents having from 2 to 20 carbon atoms, as well asaryloxy substituents. Also included are alkylthio, alkylsulfonyl, andalkylsulfinyl substituents with from 1 to 20 carbon atoms. Each of theabove classes of R or R′ substituent can be further optionallysubstituted with halogen, or with alkyl or alkoxy groups of from 1 to 10carbon atoms, or aryl groups. Further substitution of R and R¹ caninclude the functional groups of hydroxyl, thiol, thioether, ketone,aldehyde, ester, amide, amine, imine, nitro, carboxylic acid, disulfide,carbonate, isocyanate, carbodiimide, carboalkoxy, carbamate, andhalogen.

Any of the above R or R¹ substituents can include various structuralisomers (n-, iso-, sec-, and tert-), cyclic or polycyclic isomers, andmultiply unsaturated variants.

Particularly useful R and R¹ substituents are vinyl, phenyl, hydrogen,wherein the vinyl and phenyl substituents are optionally substitutedwith one or more moieties selected from C₁-C₅ alkyl, C₁-C₅ alkoxy,phenyl or a functional group, such as chloride, bromide, iodide,fluoride, nitro, or dimethylamine.

When carbon atom C¹ is not directly bonded to two groups R and R¹, it isfurther bonded to another carbon C², which is in turn bonded topreviously described substituents R and R¹, and the olefin metathesisactive carbene ligand is referred to as a vinylidene. This is shown inFIG. 1B. This ligation is generally achieved by means of a double bondfrom C¹ to C².

Also, as shown in FIG. 1C, C² can be further bonded to another carbonC³. This type of olefin metathesis active carbene ligand is referred toas an allenylidene. C³ is further bonded to the above-describedsubstituents R and R¹. Carbons C¹, C² and C³ are each sp² hybridizedcarbons, and the absence of one or two of such carbons in theallenylidene structure of FIG. 1C gives the respective vinylidene oralkylidene or FIG. 1B or 1A, respectively.

It has been found that when R or R¹ are aryl, the allenylidene ligandcan undergo a rearrangement, forming a different structure in which aring is formed between C¹ and an aryl carbon of R or R¹. For example, ifC¹═C²═C³Ph₂ is ligated to metal M in the systems described herein, theolefin metathesis active carbene ligand is not an allenylidene, butrather a cyclized vinyl carbene, an “indenylidene” (in this casephenylindenylidene).

Also ligated to metal atom Mare ligands X and X¹ which are anionicligands, shown in FIGS. 1A, 1B and 1C. Such anionic ligands includethose independently chosen from halogen, benzoate, C₁-C₅ carboxylate,C₁-C₅ alkoxy, phenoxy, and C₁-C₅ alkylthio groups. In other particularembodiments, X and X¹ are each halide, CF₃CO₂, CH₃CO₂, CFH₂CO₂,(CH₃)₃CO, (CF₃)₂(CH₃)CO, (CF₃)(CH₃)₂CO, PhO, MeO, EtO, tosylate,mesylate, brosylate, or trifluoromethanesulfonate. In other particularembodiments, both X and X¹ are chloride. Ligands X and X¹ can further bebonded to each other, forming a bidentate anionic ligand. Examplesinclude diacid salts, such as dicarboxylate salts. As discussed herein,such groups can alternatively be further bound to a solid phase, forexample a polymer support.

Also ligated to metal atom M are ligands L and L¹. These ligands arechosen from a number of different chemical classes.

One of these classes of ligands L or L¹ is the class of nucleophiliccarbenes. In the inventive catalytic complexes, at least one of theligands L or L¹ is a member of this class. Nucleophilic carbenes arethose molecules having a carbon atom which bears a lone pair ofelectrons, desirably also including those molecules additionally havingelectron-withdrawing character manifested in atoms or substituents inelectronic communication with, or bonded to, the carbon bearing the lonepair. Such electron withdrawing atoms or substituents can include atomswhich are more electronegative than carbon, such as nitrogen, oxygen,and sulfur. These atoms can either be bonded directly to the carbenecarbon, or in a conjugated or hyperconjugated position with respect tothis carbon. Substituents which have electron-withdrawing characterinclude nitro, halogen, sulfonate, carbonate, sulfide, thioether, cyano,and other groups known to those in the art.

In particular embodiments, it has been found to be desirable that notboth of ligands L and L¹ be nucleophilic carbenes, although embodimentsin which both L and L¹ are nucleophilic carbenes are also operative.

Particularly desirable are nucleophilic carbene ligands furthersubstituted with substituents which increase the steric crowding aroundthe carbon bearing the lone pair of electrons. These groups can bebonded directly to the carbene carbon, within a few atoms of the carbenecarbon, or remotely from the carbene carbon, as long as the bulky groupis able to inhibit the approach of agents which tend to react with, anddestroy the carbene, and consequently disable the catalytic complex as awhole. Thus the stability of the nucleophilic carbene ligand, and thecatalyst itself are fostered by the presence of bulky groups which areable to shield the nucleophilic carbene from reaction. It should benoted that the olefin metathesis active carbene fragment is stericallyprotected from bimolecular decomposition by the large steric umbrellaprovided by the bulky nucleophilic carbene ligand.

Although the invention is not limited by any particular mechanistictheory, it is believed that such a substituent arrangement can providesteric protection from carbene degradation pathways, including thermallyinduced degradation. The steric bulk of nucleophilic ligands asdescribed herein can lead to more thermally stable catalysts. Such bulkyor sterically hindering groups include branched alkyl groups, arylgroups, and aryl groups having branched alkyl substituents, particularlyat the ortho positions of the aryl rings. For example, a nucleophiliccarbene ligand having bulky alkyl groups such as tert-butyl, iso-propylor aryl groups with bulky alkyl groups such as 2,4,6-trialkylphenyl or2,6-dialkylphenyl interacting with the carbene, could be employed in thepresent invention. The groups L and L¹ can also be further bonded toeach other, forming a bidentate ligand wherein either one or both of Land L¹ are nucleophilic carbene ligands.

Cyclic nucleophilic carbene ligands are also envisioned. These may haveheteroatoms either in the ring, or bonded to the ring. Particularlydesirable examples of this type of nucleophilic carbene ligand are thoseligands having a carbene carbon between heteroatoms. Examples includedinitrogen rings such as imidazole, disulfur rings such as1,3-dithiolane, and dioxygen rings such as 2H, 4H-1,3-dioxine. Thearomatic, non-aromatic, saturated or unsaturated analogs can be used aswell.

FIG. 2A depicts an example of a nucleophilic carbene ligand which can beutilized in certain embodiments of the present invention. Shown is animidazol-2-ylidene having substituents Y and Y¹, and Z and Z¹. Eachsubstituent is independently selected from a number of carbon-containinggroups, or from hydrogen. The carbon-containing groups which cancomprise Y, Y¹, Z and Z¹ include alkyl groups having from 1 to 20 carbonatoms (such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,sec-butyl, and the like). Also possible are alkenyl or alkynylsubstituents having from 2 to 20 carbon atoms. The groups can alsoinclude alkoxycarbonyl substituents having from 2 to 20 carbons atoms,aryl groups, carboxylate substituents having from 1 to 20 carbon atoms,alkoxy substituents having from 1 to 20 carbon atoms, alkenyloxy oralkynyloxy substituents having from 2 to 20 carbon atoms, as well asaryloxy substituents. Each of the above classes of substituent can befurther optionally substituted with halogen, or with alkyl or alkoxygroups of from 1 to 5 carbon atoms.

Any of the above substituents can include all structural isomers (n-,iso-, sec-, and tert-), cyclic or polycyclic isomers, and multiplyunsaturated variants. It should also be noted that the presence of thedouble bond in the imidazole ring is not required for catalytic activityin the present invention. In certain embodiments, animidazolidin-2-ylidene can be used as nucleophilic carbene ligand L orL¹.

The structure in FIG. 2B is a particular example of a usefulnucleophilic carbene ligand, having both Y and Y¹ as2,4,6-trimethylphenyl, and both Z and Z¹ as hydrogen. This particularligand is referred to as 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene, or IMes. Another example of a useful nucleophiliccarbene is given in FIG. 2C, which shows a structure having both Y andY¹ as 2,6-diisopropylphenyl, and both Z and Z¹ as hydrogen. Thisparticular ligand is referred to as1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene, or IPr.

Another class of ligand which can serve as L or L¹ is the class ofphosphines. Particularly useful are trialkyl- or triarylphosphines, suchas trimethylphosphine, triphenylphosphine, triisopropylphosphine, andsimilar phosphines. The phosphines tricyclohexylphosphine andtricyclopentylphosphine are also useful, and are collectively referredto as PCy₃.

Other classes of ligands which can serve as L or L¹ are sulfonatedphosphines, phosphites, phosphinites, phosphonites, arsine, stibine, 1mmes, ethers, amines, amides, sulfoxides, carbonyls, carboxyls,nitrosyls, pyridines, and thioethers.

Other embodiments of catalytic complexes useful in the present inventionare shown in FIGS. 3A (alkylidene), 3B (vinylidene) and 3C(allenylidene), in which the analogy with the series of FIGS. 1A, 1B and1C is based on the identity of the olefin metathesis active carbeneligand, alkylidene, vinylidene and allenylidene, respectively. Theelements M, X, C¹, C², C³, R and R¹ are as described above for the firstdescribed embodiment of the inventive catalytic complex. In this secondparticular embodiment, ligand L is a nucleophilic carbene ligand, asdescribed above. In addition, since the species depicted in FIGS. 3A,3B, and 3C are all cationic complexes, an anion A⁻ is required. Thisanion can be any inorganic anion, and can also include some organicanions. Thus, A⁻ can be, for example, halide ion, SbF₆ ⁻, PF₆ ⁻, BF₄ ⁻—,AsCl₄ ⁻—, O₃SONO⁻, SO²F⁻, NSO₃ ⁻, azide, nitrite, nitrate, or acetate,and many others known to those of skill in the art.

In this embodiment, another ligand of metal M is Ar, which is anaromatic ring system, including the η⁶-bonded system. The symbol η isused to signify that all aromatic ring atoms are bonded to the metalatom. Such systems include C₆H₆ ring systems, and various alkylsubstituted C₆H₆ ring systems. Heterocyclic arene rings are alsosuitable, and these include η⁶-C₅H₅N, and alkyl substituted derivativesthereof. These rings can have substituents chosen from a wide range ofgroups including alkyl groups having from 1 to 20 carbon atoms (such asmethyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, andthe like). Also possible are alkenyl or alkynyl substituents having from2 to 20 carbon atoms. The groups can also include alkoxycarbonylsubstituents having from 2 to 20 carbons atoms, aryl groups, carboxylatesubstituents having from 1 to 20 carbon atoms, alkoxy substituentshaving from 1 to 20 carbon atoms, alkenyloxy or alkynyloxy substituentshaving from 2 to 20 carbon atoms, as well as aryloxy substituents. Eachof the above classes of substituent can be further optionallysubstituted with halogen, or with alkyl or alkoxy groups of from 1 to 5carbon atoms. For example, useful η⁶-bonded L or L¹ ligands arep-cymene, fluorene and indene.

The inventive catalytic complexes can be used as homogeneous catalysts,or are equally well suited as heterogeneous catalysts. The latterembodiment is realized by linking the catalytic complexes to a suitablesolid phase, such as a polymeric support. The solid phase can be boundto the catalytic complex either cleavably or non-cleavably. The solidphase can be a polymer which can either be a solid-state resin such as aWang resin, or a soluble polymer such as non-crosslinkedchloromethylated polystyrene (NCPS). This polymer shows excellentproperties, such as solubility in tetrahydrofuran (THF),dichloromethane, chloroform, and ethyl acetate, even at low temperatures(−78° C.). NCPS is insoluble in water and methanol. These features allowtraditional organic chemistry techniques such as solvent extraction, andmethanol precipitation. Suitable polymers include hydroxyl-containingpolymers such as Wang resin, or poly(ethylene glycol) (PEG).

The method of attachment between solid phase and catalytic complex cantake the form of a link to the ligand L or L¹ which is desirably thenucleophilic carbene ligand. This arrangement is desirable since thecatalytic complex is believed to operate by first releasing the ligandwhich is not a nucleophilic carbene, for example, by releasing aphosphine ligand. Thus, linkage to the phosphine ligand would result inloss of the solid phase-catalytic complex interaction, upon catalysis.Also considered desirable is linkage of the catalytic complex to a solidphase through the anionic ligands X and/or X¹. Thus, any linkage whichinvolves a group serving as an anionic ligand as described above can beused to attach the catalytic complex to a solid support. For example,carboxylate resins can be employed for this purpose.

The inventive catalytic complexes are air- and moisture-stable, and thuscan be used under atmospheric conditions, and even in aqueousenvironments. The stability of the catalytic substrates and productswill be the limiting factors with respect to use under such conditions.The inventive catalytic complexes are soluble in typical organicsolvents, such as tetrahydrofuran (THF), benzene, toluene, xylene,diethyl ether, dioxane, alcohols, acetonitrile, dimethylsulfoxide(DMSO), dimethylformamide (DMF), and similar solvents, but notparticularly soluble in water or methanol.

The catalytic complexes need not be used in the presence of anyinitiators or cocatalysts, although materials such as phosphine spongescan optionally be used. Those of skill in the art will recognize theidentity of the members of this class, which includes copper chloride,and Lewis acids generally, in concentrations up to those stoichiometricwith that of the catalytic complex.

Use of Catalytic Complexes in Ring-Closing Metathesis (RCM)

The catalytic complexes can be used for ring-closing metathesis. Thisreaction converts a diterminal diene (a compound having two—C^(a)═C^(b)H₂ groups, the C^(a) atoms of which are able to linktogether to form a cyclic compound with a —C^(a)═C^(a)— linkage), to acyclic alkene, with H₂C^(b)═C^(b)H₂ as a side product. In someinstances, the diterminal diene (or an α, ω diene) can undergo a1,3-hydrogen shift rearrangement (to give an α, ω-1 diene), and theproduct will be a cyclic alkene with one less methylene group in thering, and propene as a side product.

A pronounced solvent dependence of the reactivity of the presentcatalytic complexes was noticed. As can be seen from the resultscompiled in Scheme 1, reaction rates for (IMes)(PCy₃)Cl₂Ru(═CHPh) intoluene are substantially higher than those in CH₂Cl₂ (the substituent Eis —CO₂Et). Thus, the tetrasubstituted cyclohexene derivative of Scheme1 is formed in essentially quantitative yield after only 15 min if thereaction is carried out in toluene. The reaction requires 2-3 hours inCH₂Cl₂ to reach completion. This influence of the reaction medium hasbeen observed for the ruthenium carbene complexes bearing N-mesitylsubstituents on their imidazol-2-ylidene ligands. However, the relatedcomplexes having N-cyclohexyl or N-isopropyl groups do not show thiseffect.

This reactivity of (IMes)(PCy₃)Cl₂Ru(═CHPh) in toluene is impaired by atendency of the active species to promote isomerization of the doublebonds of the substrate. Thus, in Scheme 2, treatment of the pictureddiene with as little as 1.2 mol % of (IMes)(PCy₃)Cl₂Ru(═CHPh) in tolueneleads to complete consumption of the starting material within 45 min,but delivers significant amounts of the 20-membered ring in addition tothe desired 21-membered lactone. Although not wishing to be bound by anyparticular theory, the cis-cyclic alkene is believed to result from aninitial isomerization of one of the double bonds in the startingmaterial, followed by elimination of propene instead of ethylene duringring closure. This intrinsic bias for ring contraction was notsuppressed by lowering the reaction temperature. In stark contrast,however, only minute amounts of the cis-alkene are detected if thereaction is performed in CH₂Cl₂.

As can be seen from the results compiled in Table 1, the reactivities of(IMes)(PCy₃)Cl₂Ru(═CHPh) and (IMes)(PCy₃)Cl₂Ru(phenylindenylidene) inCH₂Cl₂ are sufficiently high to allow the preparation of di-, tri- andeven tetrasubsituted cyclo-alkenes in good to excellent yields. All ringsizes including medium and macrocyclic ones can be accessed. The yielddata given are the isolated yields. The reactions with yields given withsuperscript b (entries 1-4) were carried out in toluene at 80° C. Thecompound 3a refers to (IMes)(PCy₃)Cl₂Ru(═CHPh), and 3b to(IMes)(PCy₃)Cl₂Ru(phenylindenylidene). E is —CO₂Et.

TABLE 1 RCM catalyzed by (IMes)(PCy₃)Cl₂Ru(═CHPh) and(IMes)(PCy₃)Cl₂Ru(phenylindenylidene) in CH₂Cl₂ Catalyst Yield EntryProduct (mol %) (%) 1 2

3a (2%) 3b (2%) 96^(b) 97^(b) 3

3a (5%) 77^(b) (E = CO₂Et) 4

3b (2%) 89^(b) 5

3a (5%) 98 6

3a (5%) 93 7

3b (5%) 71 8

3a (1%) 64 9   10 

3a (1%)   3a (5%) 62 (R = H) 95 (R = Me) 11 

3a (2%) 72 12 

3a (3%) 82 13 

3a (4%) 71

It must be noted that most of these cyclizations cannot be carried outif the bis(phosphine) complex (PCy₃)₂Cl₂Ru(═CHPh) is used as thecatalyst. This holds true for all tetrasubstituted cases (entries 1-4and 7), the trisubstituted 8-membered ring shown in entry 10, as well asfor annulation reactions depicted in entries 5 and 6. Although themacrocyclic products (entries 11-13) can also be obtained with the useof (PCy₃)₂Cl₂Ru(═CHPh), using (IMes)(PCy₃)Cl₂Ru(═CHPh) results inshorter reaction times and allows lower catalyst loadings to beemployed. This aspect is particularly relevant with respect topentadec-10-enolide (entry 11) which is converted into the valuable,musk-odored perfume ingredient EXALTOLIDE® (=pentadecanolide) uponsimple hydrogenation.

As can be deduced from the results in Table 1, complex(IMes)(PCy₃)Cl₂Ru(═CHPh) bearing a benzylidene carbene moiety andcomplex (IMes)(PCy₃)Cl₂Ru(phenylindenylidene) with a phenylindenylideneunit are essentially equipotent pre-catalysts.

Method of Making Catalytic Complexes

The inventive catalytic complexes can be made according to the followinggeneral synthetic procedures, which are adapted from known procedures.

To synthesize a catalytic complex according to a first embodiment of theinvention, one of the two phosphine ligands of a diphosphine-ligatedruthenium or osmium catalyst is exchanged with a nucleophilic carbeneligand. For example, starting material diphosphine-ligated complexes(PCy₃)Cl₂Ru(═CHPh) and (PPh₃)Cl₂Ru(═CHPh) can be synthesized accordingto general procedures such as those given by Schwab et al., Angew. Chem.Intl. Ed. Engl., (1995) 34, 2039-41.

Ligand-exchange reactions are carried out by exposing thediphosphine-ligated complexes to nucleophilic carbene ligands, asdefined above, in suitable solvents such as THF, toluene, and the like.Reactions are generally carried out at temperatures of from about 0° C.to about 50° C., for about 15 minutes to several hours. Subsequentrecrystallization in inert solvents gives the complexes in good yieldand high purity.

The nucleophilic carbene ligands according to the invention aresynthesized according to the following general synthetic procedure.Solutions of heteroatom-containing starting material such as aniline, orsubstituted aniline, phenol or substituted phenol, benzenethiol orsubstituted benezenethiol, primary- or secondary-amines, alcohols andthiols can be prepared in solvents such as tetrahydrofuran (THF),benzene, toluene, xylene, diethyl ether, dioxane, alcohols,acetonitrile, dimethylsulfoxide (DMSO), dimethylformamide (DMF), water,and similar solvents, under an inert atmosphere. Substituents for theabove groups include alkyl groups having from 1 to 20 carbon atoms (suchas methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl,and the like). Also possible are alkenyl or alkynyl substituents havingfrom 2 to 20 carbon atoms. The groups can also include alkoxycarbonylsubstituents having from 2 to 20 carbons atoms, aryl groups, carboxylatesubstituents having from 1 to 20 carbon atoms, alkoxy substituentshaving from 1 to 20 carbon atoms, alkenyloxy or alkynyloxy substituentshaving from 2 to 20 carbon atoms, as well as aryloxy substituents. Eachof the above classes of substituent can be further optionallysubstituted with halogen, or with alkyl or alkoxy groups of from 1 to 5carbon atoms. Particularly useful are those substituents such as methyl,ethyl, propyl, and butyl, including branched isomers, and arylsubstituents at the ortho- or diortho-positions (for example, 2- or2,6-substitution for benzyl rings).

The solution is then contacted with an approximately one half ofequimolar amount (with respect to the heteroatom-containing startingmaterial) of paraformaldehyde. After heating to dissolveparaformaldehyde, the contents of the flask are acidified with anapproximately one half of equimolar amount (with respect to theheteroatom-containing starting material) of mineral acid (for example,hydrochloric acid or nitric acid).

At this stage, if a nitrogen-containing starting material(aniline-derivative or primary amine-derivative) is used, anapproximately one half of equimolar amount (with respect to theheteroatoms-containing starting material) of a dialkoxyacetaldehyde isadded drop wise after a few minutes of stirring. Thedialkoxyacetaldehyde can be dimethoxy-, diethoxy-, dipropoxy-,dibutoxy-, diphenoxy, or can be any of a number of combinations of suchalkoxy substituents such as for example methoxyethoxy, ormethoxyphenoxy. The procedure then continues as follows.

If, on the other hand, oxygen or sulfur heteroatom-containing startingmaterial is used, the above paragraph is not followed, and theprocedures from this point on are common to all starting materials.After equipping the reaction flask with a Dean-Stark trap, or similardevice, the mixture is heated to a temperature of from about 80° C. toabout 180° C., preferably from about 100° C. to about 150° C. forseveral hours (from about 5 to about 30 hours). During this time, aprecipitate forms, as the side products of water and methanol, as wellas some solvent, are removed. The reaction mixture is stirred at roomtemperature for a time ranging from about 20 minutes to about 4 hours,preferably from 1 to 3 hours. Precipitate will have formed during thistime.

The precipitate is filtered, washed with a suitable solvent, such as THFto give the nucleophilic carbene product in the form of a salt. Forexample, if aniline or substituted aniline is used, the product will bea 1,3-diarylimidazole salt. If the starting material is a primary amine,the product will be a 1,3-dialkyl imidazole salt. Either of theseproducts can be converted to the saturated heterocyclic derivative(imidazo lidine) by conventional hydrogenation techniques such asexposure to H₂ over a carbon-palladium or carbon-platinum catalyst. Suchtechniques will be recognized and known to those of skill in the art. Ifthe starting material is a phenol- or thiobenzene-derived compound, theproduct will be a dibenzoxymethane-, or dibenzthiomethane-product. Ifthe starting material is an alcohol or thiol, the product will be a1,1-bis(alkoxy)methane- or 1,1-bis(alkylthio)methane-product.

The second embodiments of the catalytic complexes of the invention areeasily made by combining a precursor species of the catalytic complexeswith an acetylene to give the allenylidene type of catalytic complex(see FIG. 3C). An example of this precursor species of the catalyticcomplex is shown below.

In this structure, metal M, and ligands X, X¹, L and Ar are defined asabove, with L being a nucleophilic carbene. This precursor species isgenerally available in the form of a dimer [ArRuCl₂]₂, which isconverted to the precursor species when the dimer is exposed to anucleophilic carbene in a suitable solvent such as THF, hexanes andother non-protic solvents. For example, the dimer [(p-cymene)-RuCl₂]₂ iscommercially available from Strem Chemicals (Newburyport, Mass.).

The acetylenes with which precursor species of the inventive catalyticcomplexes combine to form second embodiments of the invention areterminal acetylenes, and can be substituted at the y-position with alkylor aryl groups, or optionally further substituted with halogen, or withalkyl or alkoxy groups of from 1 to 10 carbon atoms, or aryl groups.Further substitution can include the functional groups of hydroxyl,thiol, thioether, ketone, aldehyde, ester, amide, amine, imine, nitro,carboxylic acid, disulfide, carbonate, isocyanate, carbodiimide,carboalkoxy, carbamate, and halogen. Particularly useful substituentsare vinyl, phenyl, or hydrogen, wherein the vinyl and phenylsubstituents are optionally substituted with one or more moietiesselected from C₁-C₅ alkyl, C₁-C₅ alkoxy, phenyl or a functional group,such as chloride, bromide, iodide, fluoride, nitro, or dimethylamine.

The invention will be further described in the following examples, whichdo not limit the scope of the invention described in the claims.

EXAMPLES

Illustrations of methods of making certain embodiments of the inventivecatalytic complexes, as well as properties thereof, are provided by thefollowing examples.

Example 1 Synthesis of IMes-HCl

A 300 mL Schlenk flask was charged with 2,4,6-trimethylaniline (10 g, 74mmol), toluene (50 mL), and paraformaldehyde (1.11 g, 37 mmol) underargon and heated to 110° C. until all the paraformaldehyde wasdissolved. The flask was then cooled to 40° C. and HCl (6.17 mL, 6N, 37mmol) was added to the reaction mixture drop wise. The mixture wasstirred at that temperature for 10 minutes before dimethoxyacetaldehyde(6.442 g, 60% wt. in water, 37 mmol) was added in drop wise fashion. Theflask was then equipped with a Dean-Stark trap and heated to 120° C. for15 hours, during which time a dark precipitate was formed and grew involume by removal of the side-products (H₂O and methanol) and some ofthe solvent through the Dean-Stark trap. The reaction mixture was thenallowed to cool to room temperature and stirred at that temperature fortwo hours. Filtration of the precipitate through a Schlenk frit, washingwith tetrahydrofuran (three times, 20 mL each wash), and drying yieldeda white solid in 60% yield, which was characterized spectroscopically aspure IMes-HCl. ¹H NMR: δ=2.12 (s, 12H, o-CH3), 2.30 (s, 6H, p-CH₃), 6.97(s, 4H, mesityl), 7.67 (s, 2H, NCHCHN), 10.68 (s, 1H, HCl).

Example 2 Synthesis of iMes

In a glovebox, a 300 mL Schlenk flask equipped with a stir bar wascharged with 20.0 g (58.7 mmol) of IMes-HCl and 120 mL of drytetrahydrofuran. The resulting suspension was stirred for 10 minutesafter which time 6.80 g (60.7 mmol) of solid potassium tert-butoxide wasadded to the suspension at room temperature in a single portion. A darkgray solution was obtained immediately. The flask was taken out of theglovebox and connected to the Schlenk line. The solution was stirred for20 minutes before all volatiles were removed under vacuum. The residuewas extracted into warm toluene (120 mL+60 mL+20 mL) and filteredthrough a medium porosity frit (filtration was rather slow), and thesolvent was removed under vacuum to obtain crystals of IMes. Theresulting product was recovered in 90% yield, and had a dark tint butwas sufficiently pure for its use in further synthesis. Furtherpurification could be achieved by recrystallization from toluene orhexane, yielding colorless crystals.

The synthesis of related carbenes1,3-bis(4-methylphenyl)imidazol-2-ylidene (ITol) and1,3-bis(4-chlorophenyl)imiadzol-2-ylidene (IpCl) was carried in ananalogous fashion.

Example 3 Synthesis of (IMes)(PCy₃)(Cl)₂Ru(═CHCH═CMe₂)

The procedure was carried out under purified and dried argon atmosphereand with dried and degassed solvents. IMes (2.1990 g, 7.221 mmol) wassuspended in 250 mL hexanes, into which (Cl)₂(PCy₃)₂Ru(═CHCH═CMe₂)(5.0718 g, 7.092 mmol) was added in one portion. The mixture was heatedfor 2.5 hours with stirring at 60° C. During this period, the formationof an orange-brown precipitate was observed. The volume of thesuspension was then reduced in vacuum to 50 mL and the suspension wascooled to −78° C. Following filtration and cold pentane washing of theresidue (2 washes, each 20 mL), the product was isolated as a brownorange microcrystalline material in 72% yield (3.97 g).

Example 4 Synthesis of (IMes)(PC)13)CbRu(═CHPh)

The procedure of Example 3 was followed, except that(Cl)₂(PCy₃)₂Ru(═CHPh) was used. This complex was soluble in a variety oforganic solvents including hydrocarbon, tetrahydrofuran, acetone,methylene chloride, and diethylether. The identity of the complex wasconfirmed by X-ray crystallography. Other embodiments will be readilysynthesized by substituting the IMes ligand with other nucleophiliccarbene ligands.

Example 5 Thermodynamic Studies

The thermodynamics of the following reaction in tetrahydrofuran (THF) atroom temperature were studied.

[Cp*RuCl]₄+4IMes→4Cp*Ru(IMes)Cl

(Cp* is η⁵-C₅Me₅) The reaction proceeds rapidly as indicated by therapid development of a deep blue color in the reaction solution. A deepblue crystalline solid was isolated in 86% yield. Nuclear magneticresonance data of the blue solid indicated the isolation of a singlespecies bearing a unique Cp* and a single carbene ligand. X-raycrystallography confirmed the formulation of Cp*Ru(IMes)Cl. An enthalpyof reaction of −62.6±0.2 kcal/mol was measured by anaerobic solutioncalorimetry in THF at 30° C. when 4 equivalents of carbene were reactedwith 1 equivalent of the tetramer, [Cp*RuCl]₄. Table 2 compares theenthalpy of similar reactions where IMes is replaced with othermoieties.

TABLE 2 Comparison of Reaction Enthalpies Relative stability Identity ofL in ΔH (kcal/mol) of reaction: of Ru—L bond Cp * Ru(L)(Cl) [Cp *RuCl]₄ + 4L → 4Cp * Ru(L)(Cl) (kcal/mol) IMes −62.6 ± 0.2 −15.6P(isopropyl)₃ −37.4 ± 0.3 −9.4 P(cyclohexyl)₃ −41.9 ± 0.2 −10.5

The IMes ligand proves to be a stronger binder to the Cp*RuCl fragmentthan PCy₃, by 5 kcal/mol. The carbene ligand is a fairly good binder butcan be displaced if a better donor ligand, such as a phosphite, is used.The phosphite reaction allows for the construction of a thermochemicalcycle which confirms the internal consistency of the calorimetric data,as shown in Scheme 3.

A further verification of the thermochemical results can be made byexamining the following hypothetical reaction.

This reaction is calculated to be exothermic by 5 kcal/mol and noentropic barrier is apparent, so the reaction should proceed readily aswritten. Indeed, upon mixing of the reagents in THF-d₈, thecharacteristic ³¹P signal of Cp*Ru(PCy₃)Cl disappears (at 11.3 ppm), andthat of free PCy₃ appears (40.4 ppm), as observed by Campion et al., JChem. Soc. Chem. Commun., (1988)278-280.

Example 6 Structural Studies

In order to gauge the steric factor inherent in the catalytic systems,structural studies were carried out on CP*Ru(IMes)Cl (FIG. 4),Cp*Ru(PCy₃)Cl (FIG. 5), and (IMes)(PCy₃)Cl₂Ru(═CHPh) (FIG. 6).Comparison was made to another sterically demanding ligand in thecomplex Cp*Ru(P^(i)Pr₃)Cl. The following crystal data was obtained. ForCp*Ru(IMes)Cl: monoclinic, space group P2_(l/c), dark blue prism,0.35×0.25×0.20, a=10.6715 (2), b=14.3501 (3), c=19.2313 (4), β-103.2670(10) deg, Z=4, R_(f)=0.0294, GOF=0.888. For Cp*Ru(PCy₃)Cl: orthorhombic,space group Pcba, dark blue prism, 0.45×0.35×0.25, a=18.9915 (6),b=15.6835 (5), c=19.0354 (6), Z=8, R_(f)=0.0392, GOF=1.132. For(IMes)(PCy₃) ChRu(═CHPh): space group P2₁2₁2₁, yellow-orange prism,a=12.718 (1), b=14.549 (1), c=26.392 (2), R_(f)=0.0616, z=4, GOF=1.038.The metrical data of Cp*Ru(P^(i)Pr₃)Cl (Campion et al., J Chem. Soc.Chem. Commun., (1988) 278-280) can be used for comparison: Ru—P, 2.383(1) Å; Ru—Cl, 2.378 (1) Å; Ru-Cp*(c), 1.771 (1) Å; Cl—Ru—P, 91.2 (1)°;Cl—Ru-Cp*(c), 129.9 (1)°; C(1)-Ru-Cp*(c), 139.9 (1)°.

The three Cp*RuCl(L) structures are similar, with the variation in Ru-Ldistances the only standout feature, but this is explainable by thedifference in covalent radii between P and C. Only slight angledistortions are observed in Cp*Ru(IMes)Cl, presumably to accommodate thebulkiness of IMes. The IMes ligand displays non-coplanar rings withtorsion angles of 78.46 (4)° between the arene ring bound to N(2) andthe imidazole ring and 78.78(5)° between the imidazole ring and thearene ring bound to N(1). The two arene rings adopt a mutually staggeredconfiguration.

A direct comparison of the steric properties displayed by IMes and PCy₃provides insight into the significant steric congestion provided by theIMes ligation. The cone angle reported for P^(i)Pr₃ and PCy₃ are 160°and 170°, respectively (Tolman, Chem. Rev. (1977) 77, 313-348). Such acone angle measurement is not straightforward in the present system.Instead, the crystallographic data can be used to determine closestcontact angles involving non-hydrogen atoms in Cp*Ru(IMes)Cl andCp*Ru(PCy₃)Cl. For the Ru-PCy₃ fragment, an angle of 96.3° is measuredusing cyclohexyl methylene carbons on adjacent cyclohexyl rings definingthe largest angle. For the Ru—P^(i)Pr₃ fragment in Cp*Ru(P^(i)Pr₃)Cl asimilar angle of 95.8° is obtained. As for the IMes fragment, twoparameters can be obtained. Angles of 150.7° and 115.3° are measured forthe <4-Me-Ru-4′-Me and <6-Me-Ru-2′-Me angles, respectively. The stericcoverage of the IMes ligand can be considered as a fence rather than acone. The increased steric congestion provided by the IMes ligandcompared to PCy₃ derives from the presence of bulky substituents on theimidazole nitrogens and, to a greater extent, from the significantlyshorter metal-carbon bond distance which brings the entire IMes ligandcloser to the metal center.

The structural analysis of (IMes)(PCy₃)Cl₂Ru(═CHPh) shown in FIG. 6reveals a distorted square pyramidal coordination with a nearly linearCl(1)-Ru—Cl(2) angle (168.62°). The carbene unit is perpendicular to theC(1)-Ru—P plane, and the carbene aryl moiety is only slightly twistedout of the Cl(1)-Ru—Cl(2)-C(40) plane. The Ru—C(40) bond distance (1.841(11) Å) is the same as that in RuCl₂(═CH-p-C₆H₄Cl)(PCy₃)₂ (1.838 (3) Å)and shorter than that in (PCy₃)₂RuCl₂(═CHCH═CPh₂) (1.851 (21) A). Whiletwo (formally) carbene fragments are present in(IMes)(PCy₃)Cl₂Ru(═CHPh), they display different Ru—C distances(Ru—C(40)=1.841 (11) and Ru—C(1)=2.069 (11) Å). These important metricalparameters clearly distinguish two metal-carbene interactions: a metalbenzylidene fragment with a formal metal to carbon double bond and ametal imidazolium carbene with a formal metal-carbon single bond. FromFIG. 6, it is also clear that the IMes ligand is sterically moredemanding than PCy₃.

Example 7 Thermal Stability Studies

In the course of catalytic testing, the remarkable air stability of theinventive catalytic complexes was observed. To gauge the robust natureof these carbene complexes in solution, their thermal stability underinert atmosphere was tested at 60° C. The relative order of stabilityfound was(IMes)(PCy₃)Cl₂Ru(═CHPh)>>(IMes)(PPh₃)Cl₂Ru(═CHPh)>(PCy₃)₂Cl₂Ru(═CHPh).After 14 days of continuous heating of toluene solutions of(IMes)(PCy₃)Cl₂Ru(═CHPh) to 60° C., no decomposition was detected (asmonitored by both ¹H and ³¹P NMR). In contrast, solutions of(PCy₃)₂Cl₂Ru(═CHPh) showed signs of decompositions after one hour, underthe same conditions.

The catalyst (IMes)(PCy₃)Cl₂Ru(═CHPh) was stable at 100° C. for 36 hoursbefore showing any indication of decomposition. Similar thermaldecomposition studies have been conducted in refluxing methylenechloride, dichloromethane, toluene, benzene and diglyme with similarresults.

Except as may be expressly otherwise indicated, the article “a” or “an”if and as used herein is not intended to limit, and should not beconstrued as limiting, the description or a claim to a single element towhich the article refers. Rather, the article “a” or “an” if and as usedherein is intended to cover one or more such elements, unless the textexpressly indicates otherwise.

Each and every patent, patent application and printed publicationreferred to above is incorporated herein by reference in toto to thefullest extent permitted as a matter of law.

It is to be understood that while the invention has been described inconjunction with the detailed description thereof, the foregoingdescription is intended to illustrate and not limit the scope of theinvention, which is defined by the scope of the appended claims. Otheraspects, advantages, and modifications are within the scope of thefollowing claims.

We claim:
 1. A method for performing an olefin metathesis reaction,comprising the step of contacting an olefin with a catalytic complex ofthe formula:

wherein M is ruthenium; R is hydrogen; R¹ is phenyl; X and X¹ areindependently selected from the group consisting of anionic ligands; Lis selected from the group consisting of phosphines, phosphites,phosphinites, phosphonites, and pyridines; and L¹ is of the formula:

wherein Y and Y¹ are each independently an aryl group substituted withhalogen, C₁-C₅ alkyl groups, or C₁-C₅ alkoxy groups; and Z and Z¹ areindependently selected from the group consisting of hydrogen, C₁-C₂₀alkyl, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl, C₂-C₂₀ alkoxycarbonyl, aryl,C₁-C₂₀ carboxylate, C₁-C₂₀ alkoxy, C₂-C₂₀ alkenyloxy, C₂-C₂₀ alkynyloxy,and aryloxy, each Z and Z¹ optionally being substituted with halogen,C₁-C₅ alkyl groups, or C₁-C₅ alkoxy groups.
 2. The method of claim 1,wherein Y and Y¹ are each independently an aryl group substituted withC₁-C₅ alkyl groups; and Z and Z¹ are independently selected from thegroup consisting of hydrogen and C₁-C₂₀ alkyl.
 3. The method of claim 1,wherein X and X¹ are each halide, CF₃CO₂, CH₃CO₂, CFH₂CO₂, (CH₃)₃CO,(CF₃)₂(CH₃)CO, (CF₃)(CH₃)₂CO, PhO, MeO, EtO, tosylate, mesylate,brosylate or trifluoromethanesulfonate; L is selected from the groupconsisting of phosphines, phosphites, phosphinites, and phosphonites; Yand Y¹ are each independently an aryl group substituted with C₁-C₅ alkylgroups; and Z and Z¹ are independently selected from the groupconsisting of hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl,iso-butyl, and sec-butyl.
 4. The method of claim 1, wherein X and X¹ arechloride; Y and Y¹ are each 2,4,6-trimethylphenyl; L is selected fromphosphines; and Z and Z¹ are independently selected from hydrogen andmethyl.
 5. The method of claim 4, wherein L is selected fromtrimethylphosphine, triphenylphosphine, triisopropylphosphine,tricyclohexylphosphine, and tricyclopentylphosphine.
 6. The method ofclaim 4, wherein L is tricyclohexylphosphine.
 7. The method of claim 4,wherein L is triphenylphosphine.
 8. The method of claim 4, wherein Z andZ¹ are hydrogen.
 9. The method of claim 8, wherein L is selected fromtrimethylphosphine, triphenylphosphine, triisopropylphosphine,tricyclohexylphosphine, and tricyclopentylphosphine.
 10. The method ofclaim 8, wherein L is tricyclohexylphosphine.
 11. The method of claim 8,wherein L is triphenylphosphine.
 12. The method of claim 1, wherein Xand X¹ are chloride; Y and Y¹ are each 2,6-diisopropylphenyl; L isselected from phosphines; and Z and Z¹ are independently selected fromhydrogen and methyl.
 13. The method of claim 12, wherein L is selectedfrom trimethylphosphine, triphenylphosphine, triisopropylphosphine,tricyclohexylphosphine, and tricyclopentylphosphine.
 14. The method ofclaim 12, wherein L is tricyclohexylphosphine.
 15. The method of claim12, wherein L is triphenylphosphine.
 16. The method of claim 12, whereinZ and Z¹ are hydrogen.
 17. The method of claim 16, wherein L is selectedfrom trimethylphosphine, triphenylphosphine, triisopropylphosphine,tricyclohexylphosphine, and tricyclopentylphosphine.
 18. The method ofclaim 16, wherein L is tricyclohexylphosphine.
 19. The method of claim16, wherein L is triphenylphosphine.